This invention relates to extracorporeal blood treatment systems, and more particularly to a system wherein heparin is removed from an extracorporeal blood flow with the use of a filter arrangement containing protamine immobilized on a blood-compatible support.
It has been estimated that nearly twenty million procedures involving extracorporeal blood circulation are performed annually. Among the variety of procedures which require such extracorporeal blood flow are hemodialysis, renal transplantation, open heart operations, plasmapheresis, and blood oxygenation. Oftentimes, such procedures are of an emergency nature since, for example, patients with acute kidney dysfunction die within seven days. Functioning renal transplants have given life to tens of thousands of patients. With respect to open heart operations, also a procedure which requires extracorporeal blood treatment, the number of such procedures performed annually has been increasing by about one person per ten thousand persons per year. Currently, approximately twenty operations per ten thousand persons are performed annually. Approximately ninety thousand therapeutic plasmapheresis procedures are carried out in the United States. The artificial lung, also known as the blood oxygenator, has become an essential life saving device used to treat patients suffering from acute respiratory failure and infants with diaphragmatic hernia. In addition to the foregoing, it is expected that new procedures which are presently in the conceptual stage, such as the implantation of artificial livers and artificial hearts will increase the number of procedures which require extracorporeal circulation.
In all of the procedures mentioned hereinabove, blood is drawn from a patient and passed through an extracorporeal device. It is a problem with such systems, however, that upon contact with the synthetic materials which form the surfaces of the extracorporeal devices, the blood's precisely regulated hemostasis is disturbed, and therefore the blood tends to clot within the device. The thrombi which are formed occlude the perfusion channels in the device. Presently, occlusion is prevented and fluid it maintained in extracorporeal circulation by the use of heparin, which is the most widely used anticoagulant. The heparin is systemically administered to the patient and the extracorporeal device prior to treatment. However, the high level of heparin required for the purpose poses a considerable hemorrhagic hazard to the patients. It has been reported that eight to thirty percent of all hemorrhagic complications occur during heparinization. Additionally, a six to ten percent incidence of coagulation abnormalities with excessive post-operative bleeding is reported in patients who have undergone open heart surgery. In patients who have a high risk of hemorrhage, bleeding complications occurred in ten percent of those who received low dose heparin treatment, and nineteen percent of those receiving regional heparin anticoagulation. It has been further estimated that nearly twenty five percent of all patients suffering from acute renal failure were subject to increased bleeding risk during and immediately following dialysis. Such complications are enhanced for elderly patients, patients with ulcers or other multiple traumata, and patients who recently have undergone cardiac or vascular surgery.
In addition to hemorrhage, there are a variety of other complications associated with heparinization, particularly when the drug is administered over a long period. These additional complications include thrombocytopenia, alopecia, arterial embolus anaphylaxis, and interference with bone repair and maintenance. It is therefore significant that heparin has been cited as the drug responsible for the majority of drug deaths in patients who are reasonably healthy.
As a result of the life-threatening nature of the hemorrhage associated with systemic heparinization, considerable effort has been directed at solving this problem. One general approach which is widely and commonly used in clinical practice includes the administration of anti-heparin compounds, such as protamine, to neutralize the anticoagulant effects of heparin. Another approach to this problem in the prior art is the development of heparin substitutes, such as prostacyclin, and new antithrombotic agents, such as low molecular weight heparins. A still further prior art approach to this problem involves the use of low-dose heparinization, or regional anticoagulation, by infusion of heparin into the blood entering the dialyzer, and subsequent neutralization of the heparin by infusion of protamine into the heparinized blood as it returns to the patient. It is also known to use regional citrate anticoagulation, in a manner similar to that discussed hereinabove, except that citrate is used as the anticoagulant agent, and calcium is used as the neutralizing agent.
One recent approach to the problem of reducing blood clotting within extracorporeal devices involves the development of new blood compatible materials with surface bound heparin for construction of the extracorporeal devices. This approach, however, requires that the entire extracorporeal unit be made of such materials, otherwise clotting will still occur in the devices. It is almost impossible to construct the entire extracorporeal unit using such materials.
A still further prior art approach to the aforementioned clotting problem involves the development of an immobilized heparinase filter to degrade heparin at the termination of extracorporeal circulation. Heparinase is an enzyme which degrades heparin specifically into relatively inactive low molecular weight fragments, and can be used to neutralize the anticoagulant effects of heparin. Heparinase is a microbial enzyme, and use of such enzymes can lead to acute or chronic immunological responses. In addition, as are most enzymes, heparinase is unstable and loses its enzymatic activity easily under physical and chemical processing. The instability of the heparinase molecule has been shown to limit the methods which can be used to immobilize the heparinase as well as the materials which can be used as biocompatible supports. Thus, the use of heparinase -imits the efficiency of the reactor during in vivo operations. In addition to the foregoing, it is extremely difficult to sterilize or to store the heparinase based enzyme reactor without suffering significant loss of the enzyme's catalytic activity. The accumulation in the body of a patient of unnatural heparin degradation products resulting from the reaction of a heparinase reactor may also pose a serious toxic threat. This is particularly disturbing in view of the fact that heparinase molecules, though covalently attached to the support material, can be slowly but continuously leached off of the support materials. It is therefore of great concern that even trace amounts of the microbial enzyme would trigger untoward immunological responses.
It stands to reason that none of the aforementioned approaches to the problem of extracorporeal clotting have met with much clinical success. For example, direct intravenous administration of protamine has been reported widely to induce serious (or even fatal) anaphylactic response. Prostacyclin infusion is associated with the unpredictable occurrence of sudden hypotension. The use of low molecular weight heparins as new anti-thrombotic agents has been restricted due to the lack of neutrailizing agents for these compounds. The use of low-dose heparinization or regional heparin anticoagulation has proved unsuccessful in preventing bleeding associated with dialysis. Moreover, regional heparin anti-coagulation does not obviate the need for protamine as the neutralizing agent. Regional citrate anticoagulation is rarely used because of the technical difficulties in performing the procedures and in determining the adequate amount of calcium required for citrate neutralization.
It is therefore, an ooject of this invention to provide a simple, economical and effective system for removing extracorporeal heparin.
It is also an object of this invention to prevent clotting when extracorporeal blood communicates with extracorporeal devices, without introducing heparin into the living being.
It is another object of this invention to reduce the possibility of hemorrhagic and other complications associated with the use of heparin.
It is a further object of this invention to eliminate the effects of heparin without introducing protamine into the living being.
It is additionally an object of this invention to remove heparin from extracorporeal blood with the use of protamine.
It is yet another object of this invention to prevent the toxic effects of protamine resulting from heparin neutralization with protamine.
It is a still further object of this invention to produce a heparin removal system which can be easily sterilized.
It is an additional object of this invention to provide a heparin removal system wherein the heparin neutralization agent is stable.
It is still another object of this invention to provide a heparin removal system which will not trigger immunological responses in living beings.
It is a yet further object of this invention to produce a heparin removal system which will not produce foreign degradation products.
It is also another object of this invention to provide an anticoagulation system which removes heparin from extracorporeal blood, rather than merely neutralize its effects.